Compositions and methods of treating skin conditions

ABSTRACT

A composition is described comprising a vitamin D analog and a retinoid, wherein: (a) the vitamin D analog is capable of binding a vitamin D receptor or being converted in vivo into a compound capable of binding a vitamin D receptor; and (b) the retinoid is selected from the group consisting of a compound capable of binding a retinoic acid receptor, retinol in a concentration of at least about 0.1% and a compound in a concentration of at least about 0.% capable of being converted in vivo into retinol. Further, methods of treating disorders characterized by abnormal cell-proliferation and/or cell-differentiation are also described.

FIELD OF THE INVENTION

[0001] The present invention relates to compositions comprising certainretinoids and vitamin D analogs useful in inducing differentiation andinhibiting undesirable proliferation of cells, such as cancer cells andskin cells. The present invention also relates to methods of using theabove compositions in the treatment of diseases and conditionscharacterized by abnormal cell differentiation and/or cellproliferation.

DESCRIPTION OF THE RELATED ART

[0002] Abnormal cell differentiation and/or cell differentiation isassociated with many conditions and diseases. For instance,hyperproliferation of epithelial cells is associated with psoriasiscauses the skin to shed itself too rapidly, every three to four days.The goal in treating psoriasis is to reduce inflammation and to slowdown rapid skin cell division.

[0003] U.S. Pat. No. 4,866,048 discloses that certain vitamin Dderivatives, in particular calcitriol (1 alpha,25-dihydroxy-vitamin D₃or) and calcipotriol are able to stimulate the differentiation of cellsand inhibit excessive cell proliferation, and it has been suggested thatthese compounds are useful in the treatment of diseases characterized byabnormal cell differentiation and/or cell differentiation such asleukemia, myelofibrosis, psoriasis and acne.

[0004] Certain retinoids are also known for their antiproliferative anddifferentiation activity. For instance, retinol (vitamin A) is anendogenous compound which occurs naturally in the human body and isessential for normal cell differentiation of certain cell types such asepithelial cells. Retinoic acid is believed to be an active derivativeof retinol. Thus, retinoic acid is believed to be more effective thanretinol and retinyl esters at providing skin benefits.

[0005] Natural and synthetic vitamin A derivatives (including retinoicacid) have been used extensively in the treatment of a variety of skinand hyperproliferation disorders. For example, retinoic acid has beenemployed to treat certain types of leukemia like acute apromyelocyticleukemia as well as a variety of skin conditions such as acne, wrinkles,psoriasis, age spots and discoloration (Vahlquist, A. et al., J. Invest.Dermatol., Vol. 94, Holland D. B. and Cunliffe, W. J. (1990), pp.496-498; Ellis C. N. et al., “Pharmacology of Retinols in Skin”, Vasel,Karger, Vol. 3, (1989), pp.249-252; Lowe, N. J. et al., Vol. 3, (1989),pp. 240-248; PCT Patent Application No. WO 93/19743). Although retinoidshave been viewed classically as cancer prevention agents, considerablelaboratory evidence supports their testing as antitumor drugs as well(Cancer Treat Rep 1987; 71: 493-515 May, 1987).

[0006] It is important to note that while clinical experience witheither retinoids or vitamin D derivatives against conditions associatedwith abnormal cell differentiation and/or cell differentiation has metwith certain amount of success in some instances, these compounds havefrequently been unable to provide the desired clinical results.

[0007] For instance, the synthetic Vitamin D, calcipotriol, or retinoicacid which are available in prescription form are somewhat useful forindividuals with localized psoriasis. However, these compound are notvery effective on most patients.

[0008] Therapeutic regimens for acne involve local and systemictherapies, although the former is indicated in the vast majority ofcases. Topical application of a variety of chemical application whichinclude mainly sulfur, resorcinol, salicylic acid, benzoyl peroxide, andretinoic acid are frequently used to treat acne. All the foregoingagents are known as “peeling” or “drying” agents which are believed toexert their therapeutical effect by causing erythema, irritation, anddesquamination of the skin to expel comedones. The therapeutic efficacyof these agents, however, is rather variable, and their utility islimited partially because of the irritation caused by their application(see U.S. Pat. No. 3,932,665). Oral formulations of retinoic acid arealso used but serious side effects are associated with the oral use ofthis compound including severe fetal malformation in pregnant women.

SUMMARY OF THE INVENTION

[0009] It is an object of the present invention to provide compositionscomprising certain vitamin D and retinoid compounds at particularconcentrations which are useful for the treatment of disorderscharacterized by abnormal cell-proliferation and/orcell-differentiation.

[0010] In one embodiment, the present invention provides a compositioncomprising a vitamin D analog and a retinoid, wherein:

[0011] (a) the vitamin D analog is capable of binding a vitamin Dreceptor or being converted in vivo into a compound capable of binding avitamin D receptor; and

[0012] (b) the retinoid is selected from the group consisting of acompound capable of binding a retinoic acid receptor, retinol in aconcentration of at least about 0.1% and a compound in a concentrationof at least about 0.1% capable of being converted in vivo into retinol.

[0013] In yet another embodiment, the present invention provides acomposition comprising retinol in a concentration of at least about 1.5%or a compound in a concentration of at least about 1.5% capable of beingconverted in vivo into retinol.

DETAILED DESCRIPTION OF THE INVENTION

[0014] In accordance with the invention, It has been surprisinglydiscovered that a composition comprising (i) a vitamin D analog; and(ii) a retinoid selected from the group consisting of a compound capableof binding a retinoic acid receptor, retinol in a concentration of atleast about 0.1% and a compound in a concentration of at least about0.1% capable of being converted in vivo into retinol, is useful intreating a subject suffering from a disorder characterized by abnormalcell-proliferation and/or cell-differentiation more effectively thaneither a composition comprising a vitamin D analog without the abovedefined retinoid or a composition comprising the above retinoid withouta vitamin D analog. Preferably, the abnormal cell proliferation isassociated with cancer cells and more preferably with skin cancer suchas melanoma. Also more preferably, the abnormal cell proliferation isassociated with cancer cells that can at least partially respond tohormone or retinoid treatment.

[0015] The present invention also provides a method of treating asubject suffering from a disorder selected from the group consisting ofpsoriasis, acne, eczema, rosacea, actinic keratosis, seborrheicdermatitis, and congenital keratinization disorders, in which anycomposition of the present invention is administered to the subject inneed of such treatment. Preferably, the disorder is psoriasis, eczema,or acne.

[0016] The present invention further provides a method of treating oneor more conditions of the skin selected from the group consisting of dryskin, photodamaged skin, age spots, aged skin, increasing stratumcorneum flexibility, wrinkles, fine lines, actinic blemishes, skindyschromias, and ichthyosis, comprising applying to the skin having saidone or more condition any composition of the present invention.Preferably, the skin condition is actinic blemishes or fine wrinkles.

[0017] For the purpose of this invention, the term “vitamin D analog” isdefined as a compound capable of binding a vitamin D receptor (notnecessarily all) or being converted in vivo into a compound capable ofbinding a vitamin D receptor (not necessarily all). The term “vitamin Danalog” includes but is not limited to vitamin D₂ and virtaminD₃derivatives such as cholecalciferol, calcifediol, calcitriol,calcipotriol, ergosterol, ergocalciferol, dihydrotachysterol, 1, 25-dihydroxyergocalciferol, 25-hydroxydihydrotachysterol, and the vitamin Danalogs disclosed in U.S. Pat. No. 4,866,048. Preferred analogs arecholecalciferol, calcifediol, calcitriol, calcipotriol and the vitamin Danalogs disclosed in U.S. Pat. No. 4,866,048. More preferred analogs arecholecalciferol, calcifediol, calcitriol and calcipotriol. Mostpreferred analogs are calcitriol and calcipotriol.

[0018] The concentration of the vitamin D analog may vary from about0.0001% to about 10% by weight of the total composition of theinvention. Preferably, the concentrations employed of vitamin D analogsthat can directly bind to the vitamin D receptors, range from about0.0001% to about 1%, more preferably from about 0.0005% to about 0.05%,still more preferably from about 0.009% to about 0.5%, yet still morepreferably from about 0.001 to about 0.008%, and most preferably atabout 0.005%.

[0019] Preferably, the concentration employed of vitamin D analogs thatcan be converted in vivo to a compound capable of binding a vitamin Dreceptor is from about 0.001% to about 10%, more preferably from about0.01% to about 8%, still more preferably from about 1% to about 6%, andmost preferably from about 2% to about 5%.

[0020] The retinoids that are capable of binding to a retinoic acidreceptor (not necessarily all) include but are not limited to manysynthetic retinoids such as etretineate, all-trans-retinoic acid,9-cis-retinoic acid, 4-oxo-retinoic acid, 4-oxo-retinol, and4-oxo-retinal. The preferred retinoid that is capable of binding toretinoic acid receptors is all-trans-retinoic acid and 4-oxo-retinol.Most preferably, 4-oxo-retinol. Preferably, the concentration of theseretinoids in the compositions of the invention ranges from about 0.001%to about 1%, more preferably from about 0.025% to about 0.1%, mostpreferably about 0.05%.

[0021] Also, for the purpose of this invention, the term “retinol”includes but is not limited to the following: 4-oxo-retinol,all-trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol,3,4-didehydro-retinol. Preferred isomers are all-trans-retinol,13-cis-retinol, 3,4-didehydro-retinol, and 9-cis-retinol. Most preferredis all-trans-retinol due to its wide commercial availability. Theconcentration employed of retinol is at least about 0.1%, preferably atleast 0.3% by weight of the total weight of the composition. Morepreferably, the concentration such retinoid is from about at 0.3% toabout 20%, more preferably from about 0.5% to about 15%, still morepreferably from about 0.5% to about 10%, still more preferably fromabout 1% to about 10%, still more preferably from about 2% to about 10%,and most preferably about 5%.

[0022] The retinoids that can be converted in vivo to a compound capableof binding a retinoic acid receptor (not necessarily all) include butare not limited to retinyl esters, 4-oxo-retinyl esters,retinyl-glucoronides, retinoicacid-glucoronides, retinal,3,4-didehydro-retinol, 13-cis-retinoic acid, 9-cis-retinoic acid. Someretinoids bind a retinoic acid receptor and can also be converted invivo to a compound capable of binding a retinoic acid receptor such as13-cis-retinoic acid, 9-cis-retinoic acid, and 4-oxo-retinol. Compoundsthat are converted spontaneously by isomerization are also included inthe compounds of the invention.

[0023] Retinyl ester is an ester of retinol and is capable of beingconverted in vivo into retinol. Retinyl esters suitable for use in thepresent invention include but are not limited to C₁-C₃₀ esters ofretinol, preferably C₂-C₂₀ esters, and most preferably C₂, C₃, and C₆esters because they are commonly available. Examples of retinyl,estersinclude but are not limited to: retinyl palmitate, retinyl formate,retinyl acetate, retinyl propionate, retinyl butyrate, retinyl valerate,retinyl isovalerate, retinyl hexanoate, retinyl heptanoate, retinyloctanoate, retinyl nonanoate, retinyl decanoate, retinyl undecandate,retinyl laurate, retinyl tridecanoate, retinyl myristate, retinylpentadecanoate, retinyl heptadecanoate, retinyl stearate, retinylisostearate, retinyl nonadecanoate, retinyl arachidonate, retinylbehenate, retinyl linoleate, and retinyl oleate.

[0024] The preferred retinyl esters for use in the present invention areretinyl palmitate, retinyl acetate, retinyl propionate and retinyllinoleate. More preferred retinyl esters are retinyl palmitate andretinyl acetate. The most preferred retinyl ester is retinyl palmitate.

[0025] The concentration employed of the retinoid that can be convertedin vivo to a compound capable of binding a retinoic acid receptor is atleast about 0.1%, preferably at least 0.3% by weight of the total weightof the composition. More preferably, the concentration such retinoid isfrom about at 0.3% to about 20%, more preferably from about 0.5% toabout 15%, still more preferably from about 0.5% to about 10%, stillmore preferably from about 1% to about 10%, still more preferably fromabout 2% to about 10%, and most preferably about 5%.

[0026] It has also been surprisingly discovered that a compositioncomprising retinol in a concentration of at least about 1.5% or acompound in a concentration of at least about 1.5% capable of beingconverted in vivo into retinol is as effective as retinoic acid intreating one or more conditions of the skin selected from the groupconsisting of dry skin, photodamaged skin, age spots, aged skin,increasing stratum corneum flexibility, wrinkles, fine lines, actinicblemishes, skin dyschromias, ichthyosis and acne. The term “retinol” andthe compounds capable of being converted into retinol has been definedabove. Preferably, for this composition, the concentration employed ofretinol or of the compound capable of being converted in vivo intoretinol is at least about 1.8%, more preferably at least about 2% byweight of the total weight of the composition. More preferably, theconcentration such retinoid is from about at 2% to about 20%, morepreferably from about 2% to about 15%, still more preferably from about2% to about 10%, and most preferably about 5%.

[0027] The compositions of the present invention are preferably topicaland/or pharmaceutical. They may be in the form of a cream, ointment, andgel. They may also comprise a cosmetically acceptable vehicle to act asa diluent, dispersant or carrier for the active components in thecomposition, so as to facilitate their distribution when the compositionis applied to the skin.

[0028] Vehicles other than water can include liquid or solid emollients,solvents, humectants, thickeners and powders. An especially preferrednonaqueous carrier is a polydimethyl siloxane and/or a polydimethylphenyl siloxane. Silicones of this invention may be those withviscosities ranging anywhere from about 10 to 10,000,000 centistokes at25° C. Especially desirable are mixtures of low and high viscositysilicones. These silicones are available from the General ElectricCompany under trademarks Vicasil, SE and SF and from the Dow CorningCompany under the 200 and 550 Series. Amounts of silicone which can beutilized in the compositions of this invention range anywhere from 5% to95%, preferably from 25% to 90% by weight of the composition.

[0029] The cosmetically acceptable vehicle will usually form from 5% to99.9%, preferably from 25% to 80% by weight of the emulsion, and can, inthe absence of other cosmetic adjuncts, form the balance of thecomposition.

[0030] An oil or oily material may be present in the claimedcompositions, together with an emulsifier to provide either awater-in-oil emulsion or an oil-in-water emulsion, depending largely onthe average hydrophilic-lipophilic balance (HLB) of the emulsifieremployed.

[0031] Various types of active ingredients may be present in cosmeticcompositions of the present invention. Various types of activeingredients may be present in cosmetic compositions of the presentinvention. Actives are defined as skin benefit agents other thanemollients and other than ingredients that merely improve the physicalcharacteristics of the composition. Although not limited to thiscategory, general examples include sunscreens and tanning agents.

[0032] Sunscreens include those materials commonly employed to blockultraviolet light. Illustrative compounds are the derivatives of PABA,cinnamate and salicylate. For example, octyl methoxycinnamate and2-hydroxy-4-methoxy benzophenone (also known as oxybenzone) can be used.Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone arecommercially available under the trademarks, Parsol MCX andBenzophenone-3, respectively. The exact amount of sunscreen employed inthe emulsions can vary depending upon the degree of protection desiredfrom the sun's UV radiation.

[0033] Another preferred optional ingredient is selected from essentialfatty acids (EFAs), i.e., those fatty acids which are essential for theplasma membrane formation of all cells (in keratinocytes, EFA deficiencymakes cells hyperproliferative). Supplementation of EFA corrects this.EFAs also enhance lipid biosynthesis of epidermis and provide lipids forthe barrier formation of the epidermis. The essential fatty acids arepreferably chosen from linoleic acid, gamma -linolenic acid, homo- gamma-linolenic-acid, columbinic-acid, eicosa-(n-6,9,13)-trienoic acid,arachidonic acid, gamma -linolenic acid, timnodonic acid, hexaenoic acidand mixtures thereof.

[0034] Emollients are often incorporated into cosmetic compositions ofthe present invention. Levels of such emollients may range from about0.5% to about 50%, preferably between about 5% and 30% by weight of thetotal composition. Emollients may be classified under such generalchemical categories as esters, fatty acids and alcohols, polyols andhydrocarbons.

[0035] Esters may be mono- or di-esters. Acceptable examples of fattydi-esters include dibutyl adipate, diethyl sebacate, diisopropyldimerate, and dioctyl succinate. Acceptable branched chain fatty estersinclude 2-ethyl-hexyl myristate, isopropyl stearate and isostearylpalmitate. Acceptable tribasic acid esters include triisopropyltrilinoleate and trilauryl citrate. Acceptable straight chain fattyesters include lauryl palmitate, myristyl lactate, oleyl eurcate andstearyl oleate. Preferred esters include coco-caprylate/caprate (a blendof coco-caprylate and coco-caprate), propylene glycol myristyl etheracetate, diisopropyl adipate and cetyl octanoate.

[0036] Suitable fatty alcohols and acids include those compounds havingfrom 10 to 20 carbon atoms. Especially preferred are compounds such ascetyl, myristyl, palmitic and stearyl alcohols and acids.

[0037] Among the polyols which may serve as emollients are linear andbranched chain alkyl polyhydroxyl compounds. For example, propyleneglycol, sorbitol and glycerin are preferred. Also useful may bepolymeric polyols such as polypropylene glycol and polyethylene glycol.Butylene and propylene glycol are also especially preferred aspenetration enhancers.

[0038] Exemplary hydrocarbons which may serve as emollients are thosehaving hydrocarbon chains anywhere from 12 to 30 carbon atoms. Specificexamples include mineral oil, petroleum jelly, squalene andisoparaffins.

[0039] Another category of functional ingredients within the cosmeticcompositions of the present invention are thickeners. A thickener willusually be present in amounts anywhere from 0.1 to 20% by weight,preferably from about 0.5% to 10% by weight of the composition.Exemplary thickeners are cross-linked polyacrylate materials availableunder the trademark Carbopol from the B. F. Goodrich Company. Gums maybe employed such as xanthan, carrageenan, gelatin, karaya, pectin andlocust beans gum. Under certain circumstances the thickening functionmay be accomplished by a material also serving as a silicone oremollient. For instance, silicone gums in excess of 10 centistokes andesters such as glycerol stearate have dual functionality.

[0040] Powders may be incorporated into the cosmetic composition of theinvention. These powders include chalk, talc, Fullers earth, kaolin,starch, smectite clays, chemically modified magnesium aluminum silicate,organically modified montmorillonite clay, hydrated aluminum silicate,fumed silica, aluminum starch octenyl succinate and mixtures thereof.

[0041] Other adjunct minor components may also be incorporated into thecosmetic compositions. These ingredients may include coloring agents,opacifiers, perfumes and preservatives (e.g., imidazolidinyl urea,dimethyl imidazolidinone and diazolidinyl urea). Amounts of thesematerials may range anywhere from 0.001% up to 20% by weight of thecomposition.

[0042] The composition according to the invention is intended primarilybut not exclusively as a product for topical application to human skinare as a product to modulate cell differentiation. In use, a smallquantity of the composition, for example from 1 to 5 ml, is applied toexposed areas of the skin, from a suitable container or applicator and,if necessary, it is then spread over and/or rubbed into the skin usingthe hand or fingers or a suitable device.

[0043] The topical skin treatment composition of the invention can beformulated as a lotion having a viscosity of from 4,000 to 10,000 mPas,a fluid cream having a viscosity of from 10,000 to 20,000 mPas or acream or a gel having a viscosity of from 20,000 to 100,000 mPas orabove. The composition can be packaged in a suitable container to suitits viscosity and intended use by the consumer. For example, a lotion orfluid cream can be packaged in a bottle or a roll-ball applicator, or acapsule, or a propellant-driven aerosol device or a container fittedwith a pump suitable for finger operation. When the composition is acream, it can simply be stored in a non-deformable bottle or squeezecontainer, such as a tube or a lidded jar.

[0044] The invention accordingly also provides a closed containercontaining a cosmetically acceptable composition as herein defined.

[0045] The following specific examples further illustrate the invention,but the invention is not limited thereto.

EXAMPLE 1

[0046] This example compares therapeutically applied retinyl palmitate,retinoic acid, calcitriol, and combinations thereof in a cream atdifferent concentrations with the effectiveness of the cream without anyof the above compounds present in treating acne. The cream used is thecommercially available LUBRIDERM cream. The different compounds atdifferent concentrations were added to the cream and mixed very well.Sixty six volunteers were recruited and were randomly assigned to eachof the groups. The subjects were selected on the basis of their havingmoderate to severe papular-pustular acne. Each group consisted of 3males and 3 females. No other acne treatment was permitted during theperiod. Preparations were applied to the face in the morning and eveningafter washing the face with ordinary soap. Observations were made attime 0, 1, 4, and 8 weeks to assure that treatment was carried outaccording to direction. Judgments of “worse”, “no change”, “mild”, and“good” were made after 8 weeks of treatment. Table 1 illustrates theresults. TABLE 1 Results of treatment with various compounds on acne noTreatment worse change mild good Control 2 4 0 0 0.1% retinoic acid 0 23 1 0.1% retinyl 2 3 1 0 palmitate 1% retinyl palmitate 0 4 2 0 1.5%retinyl 0 1 3 2 palmitate 5% retinol 0 1 2 3 10% retinol 0 0 3 3 0.0025%calcitriol 2 3 1 0.1% retinoic acid 0 1 3 2 and 0.0025% calcitriol 0.1%retinyl 1 2 2 1 palmitate and 0.0025% calcitriol 0.5% retinyl 0 1 3 2palmitate and 0.0025% calcitriol 5% retinyl palmitate 0 0 1 5 and0.0025% calcitriol

[0047] Table 1 illustrates that retinyl palmitate in concentrations atabout 1.5% and more shows a remarkable improvement over lowerconcentrations in treating acne. In addition, the combination ofretinoic acid and calcitriol shows a synergistic effect when comparedwith either retinoic acid and calcitriol. A synergistic effect is alsoseen when calcitriol is combined with retinyl palmitate particularly atconcentrations of 0.5% of retinyl palmitate.

[0048] The use of each of retinoic acid and calcitriol caused skinirritation while the use of retinyl palmitate did not.

EXAMPLE 2

[0049] This example compares therapeutically applied retinyl palmitate,retinoic acid, calcitriol, and combinations thereof in a cream atdifferent concentrations with the effectiveness of the cream without anyof the above compounds present in treating psoriasis. The cream used isthe commercially available LUBRIDERM cream. The different compounds atdifferent concentrations were added to the cream and mixed very well.Also, commercially available 0.005% calcipotriol (DOVONEX) andcommercially available 0.005% calcipotriol supplemented with 5% retinylpalmitate were employed in treating psoriasis. Two different and distantpsoriatic spots were selected on the skin of patients diagnosed withpsoriasis for different treatment. Each patient used two type of creamstwice a day, one cream on each selected spot.

[0050] Group I consisting of five patients applied on one selected spot(spot A) control LUBRIDERM cream and on the other selected spot (spot B)cream containing 0.1% retinoic acid. None of the patients showed anyimprovement in either spots even after 12 weeks of treatment.

[0051] Group II consisting of five patients applied on one selected spot(spot A) control LUBRIDERM cream and on the other selected spot (spot B)cream containing 0.1% retinyl palmitate. Three out of five patientsshowed mild improvement in itching after 3 days in spot B but noimprovement in stopping scaling which results from cellularhperproliferation. The rest of the spots showed no improvement.

[0052] Group III consisting of five patients applied on one selectedspot (spot A) control LUBRIDERM cream and on the other selected spot(spot B) cream containing 1% retinyl palmitate. Four out of fivepatients showed good improvement in itching after 3 days in spot B butno improvement in stopping scaling which results from cellularhperproliferation. The rest of the spots showed no improvement.

[0053] Group III consisting of five patients applied on one selectedspot (spot A) control LUBRIDERM cream and on the other selected spot(spot B) cream containing 5% retinyl palmitate. Five out of fivepatients showed good improvement in itching after 3 days in spot B butno improvement in stopping scaling which results from cellularhperproliferation. The rest of the spots showed no improvement.

[0054] Group IV consisting of five patients applied on one selected spot(spot A) control LUBRIDERM cream and on the other selected spot (spot B)cream containing 0.005% calcipotriol. Two out of five patients showedpartial clearance (average of 35% of spot area) in spot B after 4 weeksof treatment. However, even in the spots showing improvement and partialclearance, a certain amount of scaling is still occurring. The rest ofthe spots showed no improvement.

[0055] Group V consisting of five patients applied on one selected spot(spot A) a cream containing 0.0025% calcipotriol and on the otherselected spot (spot B) cream containing 0.0025% calcipotriol and 0.1%retinyl palmitate. One out of five patients showed partial clearance(about 20% of spot area) in spot A after 4 weeks of treatment. However,even in spot A that is showing improvement and partial clearance, acertain amount of scaling is still occurring. Two out of Five patientsshowed considerable amount of clearance (about 40% of spot area) in spotB and with little scaling and itching. The rest of the spots showed noimprovement.

[0056] Group VI consisting of five patients applied on one selected spot(spot A) a cream containing 0.0025% calcipotriol and on the otherselected spot (spot B) cream containing 0.0025% calcipotriol and 0.5%retinyl palmitate. Two out of five patients showed partial clearance(about 25% of spot area) in spot A after 4 weeks of treatment. However,even in spots A that are showing improvement and partial clearance, acertain amount of scaling is still occurring. Three out of Five patientsshowed considerable amount of clearance (about 50% of spot area) in spotB and with barely noticeable scaling and no itching. The rest of thespots showed no improvement.

[0057] Group VII consisting of five patients applied on one selectedspot (spot A) a cream containing 0.0025% calcipotriol and on the otherselected spot (spot B) cream containing 0.0025% calcipotriol and 1%retinyl palmitate. Two out of five patients showed partial clearance(about 20% of spot area) in spot A after 4 weeks of treatment. However,even in spots A that are showing improvement and partial clearance, acertain amount of scaling is still occurring. Four out of Five patientsshowed considerable amount of clearance (about 50% of spot area) in spotB and with barely noticeable scaling and no itching. The rest of thespots showed no improvement.

[0058] Group VIII consisting of five patients applied on one selectedspot (spot A) a cream containing 0.0025% calcipotriol and on the otherselected spot (spot B) cream containing 0.0025% calcipotriol and 5%retinyl palmitate. One out of five patients showed partial clearance(about 30% of spot area) in spot A after 4 weeks of treatment. However,even in spot A that is showing improvement and partial clearance, acertain amount of scaling is still occurring. Five out of Five patientsshowed considerable amount of clearance (average about 85% of spot areaand one complete clearance) in spot B and with no scaling and itching.The rest of the spots showed no improvement.

[0059] Group IX consisting of five patients applied on one selected spot(spot A) a cream containing 0.0025% calcipotriol and on the otherselected spot (spot B) cream containing 0.0025% calcipotriol and 10%retinyl palmitate. One out of five patients showed partial clearance(about 15% of spot area) in spot A after 4 weeks of treatment. However,even in spot A that is showing improvement and partial clearance, acertain amount of scaling is still occurring. Five out of Five patientsshowed considerable amount of clearance (average about 90% of spot areaand two complete clearance) in spot B and with no scaling and itching.The rest of the spots showed no improvement.

[0060] Group X consisting of five patients applied on one selected spot(spot A) a cream containing 0.005% calcipotriol and on the otherselected spot (spot B) cream containing 5% Cholecalciferol and 5%retinyl palmitate. Two out of five patients showed partial clearance(about 15% of spot area) in spot A after 4 weeks of treatment. However,even in spots A that are showing improvement and partial clearance, acertain amount of scaling is still occurring. Five out of Five patientsshowed considerable amount of clearance (average about 75% of spot areaand one complete clearance) in spot B and with no scaling and itching.The rest of the spots showed no improvement.

[0061] This data clearly indicates the synergistic effect of usingretinoic acid or retinyl esters above 0.1% particularly at higherconcentrations in treating psoriasis. Similar experiments were carriedout using retinol rather than retinyl palmitate with similar results.

EXAMPLE 3

[0062] Three patients diagnosed with eczema were treated with creamcontaining 0.0025% calcipotriol and 5% retinyl palmitate. A significantimprovement was noticed in all three patients within 5 days and two hadnormal-looking skin after two weeks.

EXAMPLE 4

[0063] Various types of human melanoma, breast cancer and prostatecancer cells will be cultured according to standardized procedures.These cells will be incubated with in the presence of variousconcentrations of retinol, retinoic acid, retinyl esters, calcitriol ora combination thereof. Cell growth of at least some of these cells willbe shown to be significantly inhibited in the presence of calcitriol andhigh concentrations of retinol (about 10⁻⁵M) as compared with cellsincubated in the absence of the above compounds or in the presence ofeach of the above compounds alone.

EXAMPLE 4

[0064] Various types of human melanoma, breast cancer and prostatecancer cells will be cultured according to standardized procedures.These cells will be incubated with in the presence of variousconcentrations of retinol, retinoic acid, retinyl esters, calcitriol ora combination thereof. Some cells will also be incubated in mediacollected from F9 mouse teratocarcinoma cells after these F9 cells wereincubated in the presence of 10⁻⁵M retinal for 12-48 hours ± calcitriol.Cell growth of at least some of these cell lines will be shown to besignificantly inhibited in the presence of calcitriol and highconcentrations of retinal (about 10⁻⁵M) or in the presence F9 culturedmedia containing calcitriol prior to incubation with F9 cells or after.

[0065] The invention has been described in terms of preferredembodiments thereof, but is more broadly applicable as will beunderstood by those skilled in the art. The scope of the invention istherefore limited only by the following claims.

What is claimed is:
 1. A composition comprising a vitamin D analog and aretinoid, wherein: (a) the vitamin D analog is capable of binding avitamin D receptor or being converted in vivo into a compound capable ofbinding a vitamin D receptor; and (b) the retinoid is selected from thegroup consisting of a compound capable of binding a retinoic acidreceptor, retinol in a concentration of at least about 0.1% and acompound in a concentration of at least about 0.1% capable of beingconverted in vivo into retinal.
 2. A topical composition according toclaim 1 .
 3. The composition of claim 1 , wherein the vitamin D analogis selected from the group consisting of cholecalciferol, calcifediol,calcitriol, calcipotriol, ergocalciferol, dihydrotachysterol,1,25-dihydroxyergocalciferol, and 25-hydroxydihydrotachysterol.
 3. Thecomposition of claim 1 , wherein the vitamin D analog is calcitriol. 4.The composition of claim 1 , wherein the vitamin D analog iscalcipotriol.
 5. The composition of claim 1 , wherein the retinoid isretinal.
 6. The composition of claim 1 , wherein the retinoid is aretinyl ester.
 7. The composition of claim 1 , wherein the vitamin Danalog is calcitriol or calcipotriol at a concentration of about 0.005%and the retinoid is a retinyl ester at a concentration of about 5%. 8.The composition of claim 6 , wherein the retinyl ester is retinylpalmitate.
 9. The composition of claim 1 , wherein the retinoid isretinal.
 10. A method of treating a subject suffering from a disordercharacterized by abnormal cell-proliferation and/orcell-differentiation, in which a composition according to claim 1 isadministered to the subject in need of such treatment.
 11. A method oftreating a subject suffering from a disorder selected from the groupconsisting of psoriasis, acne, eczema, rosacea, actinic keratosis,seborrheic dermatitis, and congenital keratinization disorders, in whicha composition according to claim 1 is administered to the subject inneed of such treatment.
 12. The method of claim 11 , wherein thedisorder is psoriasis.
 13. The method of claim 11 , wherein the disorderis eczema.
 14. The method of claim 11 , wherein the disorder is acne.15. A method of treating one or more conditions of the skin selectedfrom the group consisting of dry skin, photodamaged skin, age spots,aged skin, increasing stratum corneum flexibility, wrinkles, fine lines,actinic blemishes, skin dyschromias, and ichthyosis, comprising applyingto the skin having said one or more condition the composition of claim
 1. 16. A composition comprising retinol in a concentration of at leastabout 1.5% or a compound in a concentration of at least about 1.5%capable of being converted in vivo into retinol.
 17. A method oftreating one or more conditions of the skin selected from the groupconsisting of dry skin, photodamaged skin, age spots, aged skin,increasing stratum corneum flexibility, wrinkles, fine lines, actinicblemishes, skin dyschromias, ichthyosis and acne, comprising applying tothe skin having said one or more condition the composition of claim 16 .18. The method of claim 17 , wherein the skin condition is acne.
 19. Themethod of claim 17 , wherein the skin condition is actinic blemishes.20. The method of claim 16 , wherein the skin condition is finewrinkles.